U.S. patent application number 14/650079 was filed with the patent office on 2015-11-05 for triazine formulations with a second active ingredient and surfactant(s).
The applicant listed for this patent is CEVA SANTE ANIMALE. Invention is credited to FLORENCE GUIMBERTEAU, ANNE-CLAIRE LE MEUR.
Application Number | 20150313940 14/650079 |
Document ID | / |
Family ID | 47471627 |
Filed Date | 2015-11-05 |
United States Patent
Application |
20150313940 |
Kind Code |
A1 |
LE MEUR; ANNE-CLAIRE ; et
al. |
November 5, 2015 |
TRIAZINE FORMULATIONS WITH A SECOND ACTIVE INGREDIENT AND
SURFACTANT(S)
Abstract
The present invention is relative to novel compositions
comprising at least one active ingredient of the family of the
triazines combined with another active ingredient and specific
compounds that allow the reduction of foam formation. More
particularly, the invention relates to compositions in the form of
aqueous suspensions comprising a triazine, an iron complex, and one
or more surfactant(s) having a particular HLB.
Inventors: |
LE MEUR; ANNE-CLAIRE;
(LIBOURNE, FR) ; GUIMBERTEAU; FLORENCE;
(MONTUSSAN, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CEVA SANTE ANIMALE |
LIBOURNE |
|
FR |
|
|
Family ID: |
47471627 |
Appl. No.: |
14/650079 |
Filed: |
December 6, 2013 |
PCT Filed: |
December 6, 2013 |
PCT NO: |
PCT/EP2013/075760 |
371 Date: |
June 5, 2015 |
Current U.S.
Class: |
424/647 ;
206/219; 514/25 |
Current CPC
Class: |
A61K 47/02 20130101;
A61K 9/08 20130101; A61P 33/02 20180101; A61K 33/26 20130101; A61K
9/0095 20130101; A61K 31/53 20130101; A61K 2300/00 20130101; A61K
9/10 20130101; A61K 2300/00 20130101; A61K 33/26 20130101; A61J
1/2093 20130101; A61K 45/06 20130101; A61K 31/53 20130101 |
International
Class: |
A61K 33/26 20060101
A61K033/26; A61J 1/20 20060101 A61J001/20; A61K 31/53 20060101
A61K031/53 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 7, 2012 |
EP |
12306548.4 |
Claims
1-20. (canceled)
21. A composition comprising at least one triazine compound and a
further active ingredient, wherein said composition is an aqueous
suspension containing one or more surfactant(s) having a
Hydrophilic-Lipophilic Balance (HLB) comprised between 1 and 8.
22. The composition according to claim 21, wherein the further
active ingredient is selected from antibiotics, anti-inflammatory
agents, anthelmintics, endectocides, minerals or vitamins.
23. The composition according to claim 21, wherein the further
active ingredient is an iron complex.
24. The composition according to claim 23, wherein the iron complex
is an aqueous colloidal solution of beta-ferric oxyhydroxide and
dextran glucoheptonic acid.
25. The composition according to claim 23, wherein the iron complex
is an aqueous colloidal solution of beta-ferric oxyhydroxide and
dextran glucoheptonic acid with a non-heme iron absorption
promoter.
26. The composition according to claim 21, further comprising at
least one hydrophilic solvent and/or at least one salt and/or at
least one high HLB surfactant and/or at least one thickening agent
and/or at least one preservative.
27. The composition according to claim 21, wherein said composition
comprises: from 1% to 10% by weight of triazine(s), from 10% to 25%
by weight of an iron complex, from 0.01% to 5% by weight of one or
several surfactant(s) having an HLB of between 1 and 8, from 0% to
30% by weight of one or several hydrophilic solvent(s), from 0% to
10% by weight of one or several salt(s), from 0% to 5% by weight of
one or several high HLB surfactants, from 0% to 10% by weight of
one or several thickening agent(s), and from 0% to 10% by weight of
one or several preservative(s), with respect to the total weight of
the composition.
28. The composition according to claim 21, wherein said triazine is
a triazinetrione.
29. The composition according to claim 28, wherein said
triazinetrione is toltrazuril or diclazuril.
30. The composition according to claim 21, wherein said one or
several surfactant(s) having an HLB of between 1 and 8 is selected
from soybean lecithins, sorbitan esters, polyol esters, silicone
emulsion, simethicone emulsion, propylene glycol monolaurate,
propylene glycol monocaprylate, glyceryl monooleate, phospholipids,
lauroyl polyoxylglycerides, linoleoyl polyoxylglycerides, oleoyl
polyoxylglycerides, or polyoxyethylene alkyl ether.
31. The composition according to claim 30, wherein said one or
several surfactant(s) having an HLB of between 1 and 8 is a
simethicone emulsion.
32. The composition according to claim 31, wherein the simethicone
emulsion comprises about 25 to 35% of simethicone USP.
33. The composition according to claim 31, wherein the simethicone
emulsion comprises polydimethylsiloxane,
octamethylcyclotetrasiloxane, methylcellulose,
decamethylcyclopentasiloxane, methylated silica and sorbic
acid.
34. The composition according to claim 21, further comprising a
pharmaceutically acceptable carrier or excipient.
35. The composition according to claim 21, wherein said composition
is prepared or stored in a glass or plastic container.
36. The composition according to claim 21, wherein a single
container comprises all of the ingredients of the composition, in
admixture or in separated compartments, or wherein the ingredients
are contained in separated container(s) which are mixed prior to
administration.
37. A method for treating an infectious disease in a non-human
animal comprising administering to said animal a composition
according to claim 21.
38. The method according to claim 37, wherein said method treats
coccidiosis in swine.
39. The method according to claim 38, wherein said swine is a
piglet.
40. The method according to claim 37, wherein the composition
comprises between 1 and 60 mg of triazine and an iron complex, and
is administered by intramuscular injection.
41. A kit comprising a container comprising a composition of claim
21, and a notice.
42. A method for preparing a composition according to claim 21,
comprising providing a triazine, another active ingredient and a
surfactant having an HLB of between 1 and 8, and mixing said
ingredients in an appropriate container.
Description
[0001] The present invention is relative to triazine formulations
and the uses thereof. The invention more particularly relates to
new aqueous suspensions of a triazine comprising one or more
surfactant(s) having a particular HLB (Hydrophilic-Lipophilic
Balance). The invention also relates to compositions comprising at
least one triazine, preferably toltrazuril, and a further active
ingredient (e.g., an antibiotic, anti-inflammatory agent,
anthelmintic, endectocide, mineral or vitamin). The compositions
preferably comprise one or more surfactant(s) having a HLB
(Hydrophilic-Lipophilic Balance) comprised between 1 and 8. The
compositions are adapted for parenteral and/or oral administration.
The invention also relates to kits, methods of preparing such
compositions, as well as the uses thereof, in non-human animals
such a porcine, an ovine, a bovine, a canine, a feline or an avian
for protecting against infectious diseases, such as protozoan
disorders.
BACKGROUND OF THE INVENTION
[0002] Triazines are commonly used in the veterinary industry to
treat non-human animals against a variety of diseases. Triazines
are broad-spectrum antimicrobials that inhibit both gram positive
and gram-negative bacteria, as well as some protozoa, such as
coccidia.
[0003] Triazines, such as toltrazuril and ponazuril, are authorized
agents for the treatment and control of coccidiosis which are
frequent parasitic infectious diseases caused by protozoans such as
e.g., Eimeria or Isospora. Triazines are also effective against
other protozoal parasites e.g., toxoplasma, cryptosporidia, or
sarcocystis. They are essentially administered to the animals by
oral route. In this regard, EP116175 refers to a water miscible
solution of a triazine for oral administration. DE19603954 proposes
triazine granules for oral administration and DE19824483 relates to
semi-solid preparations which are applied orally. EP2164496 relates
to triazine-iron combination products. The triazine compound is
administered orally, as a suspension.
[0004] WO01/26660 and U.S. Pat. No. 6,465,460 relate to a sodium
salt of triazine compounds and to compositions for oral or
parenteral administration. According to this patent the sodium salt
allows the use of lower doses of the compound. Although different
administration routes are mentioned, all of the experimental
section is limited to intravenous and oral administration.
Furthermore, the patent indicates that several administrations
and/or a sustained release dose are required for maintaining
appropriate blood levels. In particular, the patent proposes a
starting dose and several maintenance doses, which need to be
administered over several days.
[0005] Despite preliminary investigations on different routes
(e.g., transdermal), oral administration is still preferred today
because it is believed to provide the most appropriate
pharmacokinetic profile of the drug, especially in young non-human
animals. In particular, while the oral formulation requires
substantive manipulation and cannot provide a strict dosage
control, it is believed to ensure appropriate bioavailability and
therapeutic efficacy of the triazine compounds.
[0006] Oral administration may, however, present drawbacks. Indeed,
oral administration cannot be conveniently combined with other
treatments which are given by injection (e.g., antibiotics,
anti-inflammatory agents, anthelmintics, endectocides, minerals or
vitamins) at early stages of growth of the non-human animal and
therefore involves additional manipulation of the non-human
animals. Oral administration may also prevents strict control of
the dosage administered to each non-human animal.
[0007] It has been proposed in the art to combine a triazine with
iron, in order to treat both coccidiosis and anemia in piglets.
However, such a combination raises formulation and administration
problems. Indeed, the triazine is usually administered orally,
while the iron compound is typically injected. EP2164196 proposed
oral compositions of both agents but, at the same time, recognizes
that iron compounds administered orally exhibit low bioavailability
and should be administered within 8 to 10 hours after birth,
leading to a separate schedule of administration for both
compounds. Moreover, it has been disclosed that depending on the
dosage or formulation, iron compound administered by injection may
cause side effects.
[0008] Accordingly, there is a need in the art for optimized
triazine formulations/administration protocols, especially for
optimized triazine/iron formulations that are efficient and
convenient. Such optimized formulations should preferably contain a
triazine (e.g., toltrazuril) and an iron complex in the same
formulation, suitable for combined administration, with dosages,
amounts, and pharmacokinetics adapted to provide effective
protection of non-human animals, even shortly after birth.
[0009] The present invention solves the above technical problems by
providing novel triazine formulations in the form of stable aqueous
suspensions with antifoaming properties, which fulfill the
conditions for a pharmaceutical use and which are adapted for oral
and parenteral administration.
SUMMARY OF THE INVENTION
[0010] An object of the invention resides in a composition
comprising a triazine compound, wherein said composition is an
aqueous suspension and comprises one or more surfactant(s) having
an HLB (Hydrophilic-Lipophilic Balance) comprised between 1 and
8.
[0011] Another object of the invention resides in a composition
comprising at least one triazine compound and another active
ingredient (preferably selected from e.g., antibiotics,
anti-inflammatory agents, anthelmintics, endectocides, minerals or
vitamins), wherein said composition is an aqueous suspension
containing at least one surfactant.
[0012] Another object of the invention resides in a composition
comprising at least one triazine compound and another active
ingredient (preferably selected from e.g., antibiotics,
anti-inflammatory agents, anthelmintics, endectocides, minerals or
vitamins), wherein said composition is an aqueous suspension
containing one or more surfactant(s) having an HLB comprised
between 1 and 8.
[0013] The compositions of the invention may optionally further
comprise at least one hydrophilic solvent and/or one or several
additional surfactant(s), and/or one or several acceptable
excipients or carriers. The compositions are preferably adapted for
oral or parenteral administration, preferably for injection such as
subcutaneous, intramuscular, intradermal or intravenous
injection.
[0014] Preferred triazine compound is a triazinetrione and, more
preferably, toltrazuril.
[0015] The further active ingredient may be selected, preferably,
from antibiotics, anthelmintics, endectocides, anti-inflammatory
agents, vitamins and/or minerals. Preferably, the further active
ingredient is an iron complex such as, without limitation, iron
dextran, iron dextran glucoheptonic acid, iron isomaltoside and
iron carboxymaltose complexes. Even more preferably, the iron
complex includes an aqueous colloidal solution of beta-ferric
oxyhydroxide and dextran glucoheptonic acid (Gleptoferron
commercialized under the trademark Gleptosil.RTM. or
Ursoferran.RTM.).
[0016] A preferred object of the invention resides in a composition
in the form of an aqueous suspension comprising (i) a triazine
compound, (ii) an iron complex, and (iii) one or more surfactant(s)
having an HLB comprised between 1 and 8.
[0017] Preferred surfactants having an HLB comprised between 1 and
8 include, without limitation, soybean lecithins, sorbitan esters,
polyol esters, silicon emulsions, simethicone emulsions, propylene
glycol monolaurate, propylene glycol monocaprylate, glyceryl
monooleate, phospholipids, lauroyl polyoxylglycerides, linoleoyl
polyoxylglycerides, oleoyl polyoxylglycerides, or polyoxyethylene
alkyl ether. Most preferred surfactants are sorbitan monooleate,
propylene glycol monolaurate and simethicone emulsion.
[0018] Preferred hydrophilic solvents are semi-polar to polar
hydrophilic solvents such as, without limitation, diethylene glycol
monoethyl ether (=Transcutol.RTM.), glycerol, polyethlene glycol
and propylene glycol.
[0019] The compositions of the invention may be prepared or stored
in various containers, preferably glass or plastic containers. The
plastic containers are preferably made such as, without limitation,
of polypropylene, polyethylene, high density polyethylene (HDPE),
polyethylene terephtalate, polyvinyl chloride, polyethylene-vinyl
acetate, polyolefins, polyesters, polyamide, or polymers.
Typically, the compositions of the invention are stored in a bottle
or flask. In a specific embodiment, the compositions of the
invention are stored in a multi-layered plastic polymeric container
comprising at least one polyolefin.
[0020] Another object of the invention is a kit comprising a
container, preferably a bottle or flask, comprising a composition
as defined above, and a notice. The container typically comprises
all of the ingredients in admixture. Alternatively, in a particular
embodiment, the container comprises two (or more) separated
compartments, each comprising distinct ingredient(s) of the
composition, which are typically mixed prior to administration.
[0021] Another object of the invention is a kit comprising two
containers, a first container comprising the triazine compound, for
instance as a powder, and a second container comprising the other
ingredient in an aqueous suspension with one or more surfactant(s)
having an HLB comprised between 1 and 8. The content of the two
containers are typically mixed prior to administration.
[0022] Another object of the invention relates to a method for
preparing a composition as defined above, comprising providing a
triazine, a further active ingredient, and a surfactant having an
HLB comprised between 1 and 8, and mixing said ingredients,
generally in an appropriate vehicle or carrier. Typically, the
method comprises (i) providing a triazine compound, preferably in
the form of a powder, (ii) providing the further active ingredient
in an aqueous suspension with one or more surfactant(s) having an
HLB comprised between 1 and 8, and (iii) mixing said ingredients in
an appropriate container. The compositions of the invention may be
prepared in advanced and stored in any appropriate container
(flask, bottle, etc.). Alternatively, the compositions may be
prepared extemporaneously, e.g., by mixing the ingredients shortly
before administration.
[0023] A further object of the invention is a composition or kit as
defined above for use to treat (e.g., prevent, retard, protect
against, reduce or cure) an infectious disease in a non-human
animal, preferably a parasitic infectious disease caused by a
protozoan.
[0024] A further object of the invention relates to a method for
treating (e.g., preventing, retarding, protecting against,
reducing, or curing) an infectious disease in a non-human animal,
preferably a parasitic infectious disease caused by a protozoan
comprising the administration of an effective amount of a
composition as defined above to the non-human animal.
Administration may be a single administration. Alternatively,
repeated administration may be performed. As indicated above, the
composition may be contained in a single container, or in two (or
more) containers which are mixed extemporaneously, for instance
shortly prior to administration.
[0025] The invention is particularly suited for protecting porcine,
ovine, bovine, canine, feline, or avian against parasitic
infectious diseases caused by protozoans. It is particularly well
adapted for the treatment of young non-human mammals such as a
bovine or a swine and more preferably a piglet newborn to 10 days
old, preferably newborn to 3 days, more preferably newborn to 48
hours.
LEGEND TO THE FIGURES
[0026] FIG. 1: Structure of preferred triazine compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention provides novel formulations comprising
at least one molecule of the triazine family and, preferably,
another active ingredient which is in the form of an aqueous
suspension, does not foam and is suitable for treating parasitic
infectious diseases caused by protozoans. More specifically, the
invention provides a composition of triazine(s) and another active
ingredient such as iron complex and a surfactant agent
characterized by an HLB (Hydrophilic-Lipophilic Balance) comprised
between 1 and 8.
[0028] The invention indeed proposes to formulate triazines and
another active ingredient (e.g., antibiotics, anti-inflammatory
agents, anthelmintics, endectocides, minerals or vitamins) as
aqueous suspensions, which provide efficient pharmacokinetic
profile. Suspensions are dispersions of the active principle(s)
solid particles (insoluble or practically insoluble) in a liquid
medium. Usually, the size of solid particles varies from one or few
nanometers to 50 micrometers. It is thus a heterogeneous mixture
made up of an external continuous liquid phase and an internal
solid phase. The use of pharmaceutical or veterinary compositions
in the form of aqueous suspensions has numerous advantages, for
example: the absorption of active ingredients comprised in a
suspension form is generally faster compared to a solid form
(tablet for example) and the chemical stability of certain active
ingredients is improved with a suspension (compared to a solution).
However, suspensions are difficult to prepare because factors which
control the physical stability of the suspensions are numerous.
Generally, the crystals of active ingredient do not have the same
density as the continuous phase of the suspension from where the
observation of creaming or sedimentation when the suspension is
left at rest. Indeed, the active particles precipitate at the end
of a certain time. It is thus necessary, before use, to stir the
suspensions in order to disperse the particles of the active
ingredient throughout the fluid phase and thus to obtain a
homogeneous sample. One of the major problems of aqueous
suspensions is the foam formation when reconstituting liquid dosage
forms after agitation, or during manufacturing processes. Such a
formation of foams (gas bubbles dispersed in the liquid) is highly
undesirable. In this regard, aqueous suspensions containing
triazines tend to form a lot of foam which, in addition to aspect
problems, does not allow to guarantee an exact dosage and can
possibly present risks of gas embolism if bubbles of air are
injected.
[0029] The present invention shows that efficient suspensions of a
triazine and another active ingredient can be prepared by adding to
the composition particular surfactants, preferably surfactants with
a low HLB (preferably between 1 and 8). By using appropriate
surfactants according to the invention, it is possible to prepare
aqueous suspensions of triazine in which foam (if formed)
disappears very quickly.
[0030] The inventors have surprisingly found that the addition of a
surfactant having a low HLB to an aqueous suspension of a triazine
with another active ingredient such as iron complex leads to a
significant foaming reduction or a total foaming suppression.
[0031] The present invention thus provides aqueous suspensions of
one or several triazine compound(s) and one or several further
active ingredient(s) in a liquid medium containing one or more
surfactant(s) with a low HLB. The compositions may in addition
further comprise one or more hydrophilic solvent(s) and/or one or
several additional surfactants, and/or one or several excipients or
carriers.
Triazine Compounds
[0032] The term "triazine(s)" designates a well-known class of
active substances, especially against infections with coccidian.
Typical triazines for use in a method or composition of the
invention are compounds of formula A or B below, of any purity,
preferably having a purity of at least 90%, as well as any salt,
ester, racemate, isomer, or prodrug, thereof:
##STR00001##
wherein
[0033] R.sup.1 is R.sup.3--SO.sub.2-- or --S--,
[0034] R.sup.2 is alkyl, alkoxy, halogen or
SO.sub.2N(CH.sub.3).sub.2,
[0035] R.sup.3 is an haloalkyl
[0036] R.sup.4 and R.sup.5 are independently from each other a
hydrogen or Cl atom; and
[0037] R.sup.6 is fluorine or chlorine,
[0038] Triazine compounds include more preferably triazinediones
(formula A) and triazinetriones (formula B). Examples of
triazinediones include, without limitation, clazuril (R.sup.4 is
Cl, R.sup.5 is H, R.sup.6 is Cl in formula A), diclazuril (R.sup.4
is Cl, R.sup.5 is Cl, R.sup.6 is Cl in formula A) or letrazuril
(R.sup.4 is Cl, R.sup.5 is Cl, R.sup.6 is F in formula A).
Preferred 1,2,4-triazinediones are diclazuril and sulazuril.
[0039] Triazines for use in the present invention are, more
preferably, triazinetriones of formula B, even more preferably
wherein R.sup.2 is a C1 to C4 alkyl or alkoxy group (e.g., methyl,
ethyl, or n-propyl), and/or R.sup.3 is a C1 to C3 perfluoroalkyl
group (e.g., trifluoromethyl).
[0040] Specific and most preferred triazines of the invention are
toltrazuril (R.sup.1=R.sup.3--S--, R.sup.2=CH.sub.3,
R.sup.3=CF.sub.3 in formula B) and ponazuril
(R.sup.1=R.sup.3--SO.sub.2--, R.sup.2=CH.sub.3, R.sup.3=CF.sub.3 in
formula B).
[0041] Toltrazuril (1-methyl-3- [3-methyl-4-
[4-(trifluoromethyl)tio)phenoxil]phenyl]-1,3,5-triazine(1H,3H,5H)-2,4,6-t-
rione) is widely used in porcine, ovine, bovine and avian for the
prevention and treatment of coccidiosis, by oral administration. It
is currently available on the market as Cevazuril.RTM. or
Baycox.RTM.. Methods for the preparation of toltrazuril are
disclosed in various patents such as U.S. Pat. No. 4,219,552, U.S.
Pat. No. 5,219,853, EP 0 201 030, and EP 0 879 057. The chemical
structure of toltrazuril is represented in formula (C) below:
##STR00002##
[0042] The chemical structures of further examples of triazine
compounds for use in the present invention are depicted in FIG.
1.
[0043] The triazine(s) are present in the composition of the
invention preferably in the amount from 1% to 10% by weight of the
total weight composition. Preferentially, the compositions contain
from 1% to 6% of one or more triazine compound(s), and even more
preferentially from 2% to 5% of one or several triazine
compound(s). The compositions preferably contain only one triazine.
The most preferred triazine compound according to the invention is
toltrazuril, the percentage of which in the composition of the
invention is comprised between 1% and 6% by weight, and even more
preferably between 2 and 5%.
[0044] The triazine(s) as defined is the present invention
comprise(s) their salts, such as for example sodium salts.
Other Active Ingredient(s)
[0045] As indicated above, the compositions of the invention
preferably combine a triazine and another active agent, which may
be selected preferably from antibiotics, anti-inflammatory agents,
anthelmintics, endectocides, minerals or vitamins.
[0046] Antibacterial antibiotics are commonly classified based on
their mechanism of action, chemical structure, or spectrum of
activity. Most target bacterial functions or growth processes.
Those that target bacterial cell wall (penicillins and
cephalosporins) or cell membrane (polymixins), or interfere with
essential bacterial enzymes (rifamycins, lipiarmycins, quinolones,
and sulfonamides) have bactericidal activities. Those that target
protein synthesis (aminoglycosides, macrolides, and tetracyclines)
are usually bacteriostatic. Further categorization is based on
their target specificity. "Narrow-spectrum" antibacterial
antibiotics target specific types of bacteria, such as
Gram-negative or Gram-positive bacteria, whereas broad-spectrum
antibiotics affect a wide range of bacteria. Following a 40-year
hiatus in discovering new classes of antibacterial compounds, four
new classes of antibacterial antibiotics have been brought into
clinical use: cyclic lipopeptides (such as daptomycin),
glycylcyclines (such as tigecycline), oxazolidinones (such as
linezolid) and lipiarmycins (such as fidaxomicin). Preferred
antibiotics are aminoglycosides, such as neomycin, beta-lactam
antibiotics such as ampicillin and amoxicillin, macrolides such as
spiramycin and tylosin, polymixins, such as colistin and family of
chloramphenicol, such as chloramphenicol, thiamphenicol and
florfenicol.
[0047] Anti-inflammatory agents refers to the property of a
substance or treatment that reduces inflammation and for example
but not limited to steroids (e.g. glucocorticoids,
corticosteroids), non-steroidal anti-inflammatory drugs (NSAIDs) or
immune selective anti-inflammatory derivatives (ImSAIDs).
[0048] Anthelmintics are drugs that are used to treat infections
with parasitic worms. This includes both flat worms, e.g., flukes
and tapeworms and round worms, i.e., nematodes. They are separated
into classes on the basis of similar chemical structure and mode of
action such as for example but not limited to piperazine,
flubendazole, benzimidazole, oxybendazole, nicotinic receptor
agonists (levamisole, pyrantel and morantel), oxindole alkaloid
(paraherquamide A and marcfortine A), macrocylic lactones and
milbemycins, cyclodepsipeptide molecule (emodepside) and pyruvate
ferredoxin oxidoreductase inhibitor (nitazoxanid).
[0049] Endectocides are used in the treatment and control of
internal (endo-) and external (ecto-) parasites in certain animals.
Endectocides comprise two groups of closely related compounds, the
avermectins such as but not limited to doramectin, eprinomectin,
and ivermectin and the milbemycin such as but not limited to
moxidectin.
[0050] Vitamins are organic compounds required by an animal as a
vital nutrient in limited amounts such as but not limited to
Vitamin A, Vitamin B1 to 12, vitamin C, etc.
[0051] Minerals are trace elements, micronutrients or ions such as
but not limited to calcium, copper, magnesium, selenium or iron.
Generally minerals are elements known by a skilled person in the
veterinary field according to the needs of each non-human animal
treated. A preferred mineral for use in the invention is an iron
complex.
Iron Complexes
[0052] Because iron salts may be toxic at high concentrations, the
iron is preferably complexed to a macromolecule, such as
carbohydrate or polymer. For example we can cite iron dextran,
glucoheptonic acid of iron dextran, iron isomaltoside, iron
carboxymaltose iron-sucrose, iron-oligosaccharide and
iron-gluconate compounds. Examples of other preferred iron
complexes include, without limitation, an aqueous colloidal
solution of beta-ferric oxyhydroxide (or ferric hydroxide) and
dextran glucoheptonic acid (Gleptoferron commercialized under the
trademark Gleptosil.RTM. or Ursoferran.RTM.) or a ferric hydroxide
with a low molecular weight dextran (commercialized under the
trademark Uniferon.RTM. or Dexafer.RTM.) or a ferric hydroxide with
macromolecular dextran (commercialized under the trademark
Ferroforte.RTM.) or a ferric compound of type I.
[0053] The iron (as complex) represents preferably from 10% to 25%
by weight of the total weight of the composition. Preferentially,
the compositions of the invention contain from 10% to 20% of iron
(as complex(es)), and even more preferentially from 12% to 20% of
iron (as complex(es)). The most preferred iron complex for use in
the invention is a colloidal solution of beta-ferric oxyhydroxide
(or ferric hydroxide) and dextran glucoheptonic acid
(Gleptoferron), the percentage of iron (as complex) in the
compositions of the invention may be comprised between 12% and 20%
by weight. Advantageously, the iron complex used may contain an
effective amount of promoters of non-heme iron absorption, such as
but not limited to vitamin C (ascorbic acid), derivatives of
ascorbic acid, such as ascorbyl palmitate, an ester synthetic
compound of palmitic acid with L ascorbic acid (vitamin C
palmitate, or erythorbic acid).
Surfactants
[0054] The term "surfactant" designates an agent which modifies the
liquid surface tension, in particular that of water.
[0055] Preferred surfactants of the invention are surfactants
having a low HLB (Hydrophilic-Lipophilic Balance), more preferably
a HLB ranging from 1 to 8. The invention shows that such particular
class of surfactants allows the formation of suspensions of a
triazine and another active ingredient which do not form foam upon
stirring or in which foam (if formed) disappears very quickly.
[0056] A surfactant molecule can be described as a hydrophobic
chain (affinity for nonpolar solvents) linked to a hydrophilic
chain (affinity for polar solvents). Consequently, surfactants
present antagonistic properties and, once formulated in water, the
hydrophobic part rejects the molecule on the surface and the
hydrophilic part tends to plunge within the liquid.
[0057] The HLB is used to determine the hydrophilic or hydrophobic
dominant character of a surfactant. HLB values have been proposed
in 1949 by Griffin (Griffin W C, Surface-Active Classification of
Agents by HLB, Newspaper of the Society of Cosmetic Chemists 1
(1949): 31). This method allows the determination of reference
points which quantify existing balance between the hydrophilic part
and the lipophilic part of the molecule of surfactant, and which
are related to its solubility in water. The scale varies from 0 to
40: the higher the value of HLB, the bigger is the solubility in
water.
[0058] In 1957, Davies suggested a method based on calculating a
value based on the chemical groups of the molecule. The advantage
of this method is that it takes into account the effect of stronger
and weaker hydrophilic groups. According to the method of
Davies:
HLB=.SIGMA.HLB.sub.groupes hydrophiles-.SIGMA.HLB.sub.groupes
hydrophobes+7.
[0059] Preferred surfactants of the invention are hydrophobic with
a low HLB, more preferably ranging from 1 to 8, typically of 1, 2,
3, 4, 5, 6, 7, or 8. The surfactants for use in the compositions of
the invention are selected but not limited to soybean lecithins,
sorbitan esters, polyol esters, silicone emulsion, simethicone
emulsion, propylene glycol monolaurate, propylene glycol
monocaprylate, glyceryl monooleate, phospholipids, lauroyl
polyoxylglycerides, linoleoyl polyoxylglycerides, oleoyl
polyoxylglycerides, or polyoxyethylene alkyl ether. Most preferred
surfactants are sorbitan monooleate, propylene glycol monolaurate
and simethicone emulsion.
[0060] In a particular embodiment, the preferred surfactant is a
simethicone emulsion, which typically comprises about 25 to 35% of
simethicone USP by weight. In a specific example, the simethicone
emulsion contains the following constituents: polydimethylsiloxane,
octamethylcyclotetrasiloxane, methylcellulose,
decamethylcyclopentasiloxane, methylated silica and sorbic
acid.
[0061] The surfactant(s) are preferably present in the compositions
to a total amount of 0.01 to 5% by weight of the total weight of
the composition. Preferentially, the compositions contain from 0.05
to 3% of surfactant with a low HLB, and even more preferentially
from 0.05 to 1%.
[0062] The surfactants of the invention are efficient to prevent
foaming by lowering surface tension and cohesive binding of the
liquid phase. They are also compatible with triazines and another
active ingredient, and can for stable aqueous suspensions which are
particularly adapted.
[0063] In this regard, another object of the invention resides in
the use of a surfactant having a HLB between 1 and 8 to prevent
foaming in a triazine and iron complex aqueous suspension.
[0064] Another object of the invention resides in a method for
reducing foaming in an aqueous triazine suspension with another
active ingredient, preferably iron complex, comprising adding to
the suspension an effective amount of a surfactant having a HLB
between 1 and 8.
[0065] The term "prevent foaming" and "reduce foaming" designates
aqueous suspension which do not form foam upon stirring or in which
foam (if formed) disappears very quickly.
Optional High HLB Surfactants
[0066] In particular embodiments, in addition to the low HLB
surfactant as defined above, the compositions of the invention also
contain a further surfactant, particularly a high HLB surfactant.
The addition of such a high HLB surfactant in the suspension can
further improve triazine incorporation into the final formulation.
A high HLB surfactant is a surfactant having a HLB strictly
superior to 8.
[0067] Preferred high HLB surfactants are selected but not limited
to polyethylene castor oil derivatives, polyoxyethylene alkyl
ether, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene
stearate, sodium lauryl sulfate, sodium docusate, cetrimide,
phospholipids, or cethylpyridinium chloride.
[0068] Usually, high HLB surfactant(s) constitute(s) from 0% to 5%
by weight, with respect to the total weight of the composition.
Preferentially, when present, the high HLB surfactant(s)
represent(s) from 0.05% to 5% of the composition, preferably from
0.05 to 1%.
Solvents
[0069] The composition according to the invention may optionally
comprise one or more additional hydrophilic solvents. The
hydrophilic co-solvents are used e.g., in order to reduce the time
of wetting and the time of dispersal of the aqueous suspension.
[0070] Preferred solvents are hydrophilic semi polar to polar
solvents. Preferentially, the solvents are selected but not limited
to diethylene glycol monoethyl ether, glycerol, polyethlene glycol
and propylene glycol.
[0071] Usually, the hydrophilic solvent(s) constitute(s) constitute
from 0% to 30% by weight, with respect to the total weight of the
composition. Preferentially, when present, the solvent(s)
represent(s) from 1% to 30% of the composition, preferably from 1
to 20%, even more preferentially from 1% to 15%.
Salts
[0072] The composition according to the invention may optionally
comprise one or several salts. Salts are used in order to complete
surfactant efficiency.
[0073] Preferred salts are selected but not limited to calcium
gluconate, calcium phosphate, calcium chloride, calcium sulfate,
calcium carbonate, magnesium gluconate, magnesium phosphate,
magnesium chloride, magnesium sulfate, magnesium carbonate,
potassium phosphate, potassium gluconate, potassium chloride,
potassium sulfate, potassium carbonate, sodium gluconate, sodium
chloride, sodium carbonate, sodium phosphate, sodium citrate,
sodium sulfate, ammonium chloride, or ammonium carbonate.
[0074] Usually, salt(s) represent from 0% to 10% by weight, with
respect to the total weight of the composition. Preferentially,
when present, the salt(s) represent(s) from 0.1% to 10% of the
composition, preferably from 0.5 to 4%, even more preferentially
from 0.5% to 2%.
Preservatives
[0075] The composition according to the invention may optionally
comprise one or several preservatives. Preferred preservatives are
selected but not limited to ethanol, benzoic acid and the sodium or
potassium salts thereof, chlorobutanol, benzyl alcohol,
phenylethanol, the methyl, ethyl, propyl or butyl
p-hydroxybenzoates, phenol, m-cresol, p-chloro-m-cresol or
benzalkonium chloride.
[0076] Usually, preservatives represent from 0% to 10% by weight of
the composition. Preferentially, when present, the preservative(s)
represent(s) from 0.05% to 5%, preferably, from 0.1% to 3%.
Thickeners
[0077] The composition according to the invention may optionally
comprise one or several thickeners. Preferred thickeners are
selected but not limited to octyldecanol, aluminium monostearate,
calcium phosphate, sodium phosphate, chitosan, dextran, glyceryl
behenate, glyceryl monoleate, glyceryl monostearate, colloidal
silicon dioxide, cellulose and its derivatives, starch, propylene
carbonate, hydroxypropyl methylcellulose, polyvinylpyrrolidone,
sorbitol, trehalose or sucrose.
[0078] Usually, thickeners represent from 0% to 10% by weight of
the composition. Preferentially, when present, the thickener(s)
represent(s) from 0.05% to 5%, preferably, from 0.05% to 2%.
Preferred Compositions of the Invention
[0079] The present invention provides optimized combined
compositions comprising a triazine with another active ingredient,
both suspended in an aqueous medium containing one or more specific
surfactants. Furthermore, the invention provides optimal dosages
and administration routes for all the compounds, in order to confer
best protective effect during the treatment procedures.
[0080] Preferred compositions of the invention comprise one
triazine and one iron complex, which may be combined with one or
several, preferably one, surfactant having a low HLB. Most
preferred compositions comprise a further hydrophilic solvent.
[0081] A particular object of the invention resides in an oral or
injectable composition comprising: [0082] from 1% to 10% by weight
of a triazine, preferably a triazinetrione, more preferably
toltrazuril; [0083] from 10% to 25% by weight of an iron (as a
complex), preferably Gleptoferron; [0084] from 0.01% to 5% by
weight of one or several surfactant(s), preferably sorbitan
monooleate, propylene glycol monolaurate or a simethicone emulsion;
[0085] from 0 to 30% by weight of one or several hydrophilic
solvent(s); [0086] from 0 to 10% by weight of one or several
salt(s); and [0087] from 0 to 5% by weight of one or several high
HLB surfactant(s).
[0088] In a particular embodiment, the composition further
comprises: [0089] from 0% to 10% by weight of one or several
thickening agent(s), and [0090] from 0% to 10% by weight of one or
several preservative(s).
[0091] The above weight % are provided by reference to the total
weight of the composition.
[0092] Another particular object of the invention resides in an
oral or injectable composition comprising: [0093] from 1% to 6% by
weight of a triazine, preferably a triazinetrione, more preferably
toltrazuril; [0094] from 10% to 20% by weight of an iron (as
complex, preferably Gleptoferron); [0095] from 0.05% to 3% by
weight of one or several surfactant(s), preferably selected
sorbitan monooleate, propylene glycol monolaurate or simethicone
emulsion; [0096] from 0% to 20% by weight of one or several
hydrophilic solvent(s), typically from 1% to 20%; [0097] from 0% to
4% by weight of one or several salt(s), typically from 0.5% to 4%;
[0098] from 0% to 4% by weight of high HLB surfactant, typically
from 0.05% to 4%, [0099] from 0% to 5% by weight of one or several
thickening agent(s), typically from 0.05% to 5%, and [0100] from 0%
to 5% by weight of one or several preservative(s). [0101] The above
weight % are provided by reference to the total weight of the
composition.
[0102] In another further preferred embodiment, the composition
according to the invention is an aqueous suspension comprising:
[0103] from 2% to 5% by weight of toltrazuril, [0104] from 12% to
20% by weight of an iron complex (as Gleptoferron), [0105] from
0.05% to 1% by weight of one or several surfactant(s), preferably
selected from sorbitan monooleate, propylene glycol monolaurate or
simethicone emulsion, [0106] optionally from 1 to 15% by weight of
one or several hydrophilic solvent(s), [0107] from 0% to 2% by
weight of one or several salt(s), [0108] from 0% to 2% by weight of
high HLB surfactant, [0109] from 0% to 2% by weight of one or
several thickening agent(s), and [0110] from 0% to 3% by weight of
one or several preservative(s). [0111] The above weight % are
provided by reference to the total weight of the composition.
[0112] A specific example of a composition of the invention
comprises 2.9% toltrazuril, 18.8% of iron (as Gleptoferron), 0.3%
of sorbitan monooleate, 0.1% of copolymer Polyoxyl 35--hydrogenated
castor oil, 1.5% of sodium chloride and water.
[0113] Another specific example of a composition of the invention
comprises 4.2% toltrazuril, 13.5% of iron (as Gleptoferron), 0.3%
of sorbitan monooleate, 0.1% of copolymer Polyoxyl 35--hydrogenated
castor oil, 1.5% of sodium chloride and water.
[0114] Another more specific example of a composition of the
invention comprises 4.2% toltrazuril, 13.5% of iron (as
Gleptoferron), 1% of sodium chloride, 1% of polyvinylpyrrolidone,
0.6% of phenol, 0.5% of colloidal silicon dioxide, 0.1% of sodium
docusate, 0.1% of simethicon emulsion and water.
[0115] Further specific examples of preferred compositions of the
invention are formulations 2-14 as disclosed in the examples.
[0116] Such compositions contain the amount of triazine and other
active ingredient which are required to obtain the minimal
effective dose to ensure efficient protection.
[0117] The compositions of the invention generally comprise water,
qsp 100%. They may also contain additional excipients or vehicles,
as will be disclosed below.
Preferred Administration Route and Excipients
[0118] The compositions of the invention are suitable for oral or
parenteral administration.
[0119] In this regard, the compositions may further comprise
additional veterinary acceptable excipient(s) such as surfactant
with low HLB, diluents, solvents, salts, solubilizers, adjuvants,
stabilizers, surfactants such as high HLB, antioxidants,
preservatives, thickeners.
[0120] Powders, dispersible powders, or granules suitable for
preparation of an aqueous suspension by addition of water are
convenient dosage forms for oral or parenteral administration.
Formulation as a suspension provides the active ingredient in a
mixture with a surfactant, and, optionally, with a dispersing or
wetting agent, suspending agent, and, one or more
preservatives.
[0121] The compositions of the invention may also be administered
parenterally by injection (e.g., intramuscular, subcutaneous,
intravenous, or the like), infusion or implantation in dosage
forms, formulations, or via suitable delivery devices or implants
containing conventional, non-toxic pharmaceutically acceptable
carriers and adjuvants.
[0122] The preferred administration route of the compositions of
the invention is by injection. The intramuscular administration
route is most preferred.
[0123] The compositions of the invention may be administered by
injection(s) using techniques and/or devices known per se in the
art. In this regard, injection, such as intramuscular injection can
be performed with a syringe, a gun, a micro-needle injection
device, a needle-free injection device, a pulse device, etc. In a
preferred embodiment, injection is performed with a needle injector
or a syringe. In another particular embodiment, injection is
performed with a needle-free injection device such as a pulse
needle-free system, more particularly a spring-powered,
battery-powered, or compressed-gas-powered device. Specific
examples of needle free technologies are described e.g., in
WO2006/058426, WO2007/140610, or WO2009/111794. A preferred
needle-free injection device for use in the present invention is
AcuShot.TM. needle free technology described in the international
patents WO2006/058426 and WO2007/140610.
[0124] Intramuscular injection may be made in any muscle. For
livestock, such as cattle, intramuscular injection is preferably
made in the area of the neck, or behind the ear, rather than in the
hind limb/ham muscle or in the inguinal fold.
[0125] In this regard, a particular object of the invention resides
in a use of the composition as described above, in the treatment of
coccidiosis in animal, wherein said composition is administered by
intramuscular injection in the neck or behind the ear for non-human
mammals and in muscles adjacent to the breast-bone of adult
avian.
[0126] Another particular object of the invention resides in the
use of a composition as described above, in the treatment of
coccidiosis in avians, particularly in young avians, wherein said
composition is administered by subcutaneous injection.
[0127] The compositions of the invention are more preferably
administered by a single injection to the non-human animal
[0128] The dose of triazine may vary depending on the animal
species and nature of the triazine. Conventional dosage rates from
1 to 60 mg of triazine per kg bodyweight (mg/kg) of the non-human
mammals may be used, preferably 5 to 50 mg/kg, and more preferably
from 10 to 30 mg/kg. Illustrative dosages in the compositions of
the invention are 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg
toltrazuril/dose.
[0129] Within the context of the invention, the term "effective
amount of" designates, preferably, a dose of the active agent which
produces a clinical benefit in the treated non-human animals.
Particularly, an effective amount is an amount sufficient to reduce
infection, disease development, or to improve the symptoms.
[0130] Preferred dosages for intramuscular toltrazuril are
disclosed below, for some non-human animals 1 species example:
[0131] pigs: 20 mg/kg bodyweight/treatment (preferably one single
administration); [0132] cattle: 15 mg/kg bodyweight/treatment
(preferably one single administration); [0133] sheep: 20 mg/kg
bodyweight/treatment (preferably one single administration); [0134]
poultry: 25 mg/kg bodyweight/treatment (preferably one single
administration).
Uses of Compositions of the Invention
[0135] The compositions of the invention may be used for the
treatment of any non-human animals. The term treatment includes,
particularly, the preventive treatment of non-human animal against
a disease. The preventive treatment of a non-human animal against a
disease designates a treatment made before the non-human animal has
been exposed to or in contact with the causative agent of the
disease (e.g., a pathogen, virus, protozoan, cell, etc.), or after
said exposure/contact but before development of the symptoms or at
an early stage of development of the disease. Also, the term
preventive treatment, in relation to a population of non-human
animals, designates the treatment of all members of the population
even after the disease has been detected in certain members, to
limit or avoid spreading of and contamination to the others. The
term treatment or preventive treatment also includes the
alleviation of the symptoms, as well as a delay, reduction or cure
of an existing infection.
[0136] The term treatment also includes an increase in the welfare
of the treated non-human animals, for example in increasing the
production of meat, milk, wool, etc.
[0137] The invention may be used to treat (e.g., protect, prevent,
delay, reduce or cure) an infectious disease in non-human animals,
preferably a protozoan or microbial disease. The invention is
particularly suited to treat protozoan diseases of the blood and
tissues (such as babesiosis, sarcocystosis, or toxoplasmosis), or
of the digestive tract (such as coccidiosis).
[0138] The invention may be used, in particular, to treat
coccidiosis, particularly to prevent or protect non-human animals
against coccidiosis.
[0139] In a particular embodiment, diseases which may be
efficiently treated with compositions of the invention, are
coccidiosis and protozoal diseases, which are very frequent
parasitic infectious diseases caused by coccidian protozoa such as,
e.g. Eimeria, Isospora, Neospora, Sarcosporidia, cryptosporidium,
Hammondia, besnoitia, hepatozoon and Toxoplasma. Coccidiosis is
frequent. Thus, for example, protozoans from the genera cause
coccidioses and protozoal diseases all over the world.
[0140] The predominant sign of coccidiosis is diarrhea, which
usually persists for 4 to 6 days. The faeces may vary from white to
yellow in color and from a fluid to a pasty consistency, usually
without the presence of blood. Coccidiosis predisposes the
non-human animal to the incidence of secondary bacterial infections
and severely affected non-human animal may die.
[0141] Although the morbidity is usually high, mortality is
variable, probably due to the difference in the number of oocysts
ingested, differences in the environment and the presence of other
co-existing disease problems. Although the disease has only a
slight influence on mortality, it does influence the presence of
concomitant infections and the amount of antibiotics needed to
control them. The disease also drastically affects the development
of non-human animals, where the daily weight gain of the infected
non-human animals decreases compared to uninfected non-human
animals, causing herds to have poor uniformity at weaning age.
There is notable emaciation and stunting. coccidiosis reduces
growth by about 15% on average, that is, minimum 500 g at weaning
age, and this contributes to weaning herds that are highly
heterogenous.
[0142] The compositions of the invention may be used, in
particular, to treat coccidiosis and protozoal diseases caused by
various protozoans such as, more particularly, Mastigophora
(Flagellata), Sarcomastigophora (Rhizopoda), Myxospora, Microspora,
or pneumocystis carinii. Specific examples of Mastigophora include
Trypanosomatidae such as, without limitation, Trypanosoma brucei,
T. gambiense, T. rhodesiense, T. congolense, T. cruzi, T. evansi,
or T. equinum. Specific examples of Sarcomastigophora (Rhizopoda)
include Entamoebidae and Apicomplexa (Sporozoa) such as Eimeridae,
for example E. acervuline, E. adenoides, E. alabahmensis, E.
anatis, E. anseris, E. arloingi, E. ashata, E. auburnensis, E.
bovis, E. brunetti, E. canis, E. chinchillae, E. clupearum, E.
columbae, E. contorta, E. crandalis, E. debliecki, E. dispersa, E.
ellipsoidales, E. falciformis, E. faurei, E. flavescens, E.
gallopavonis, E. hagani, E. intestinalis, E. iroquoina, E.
irresidua, E. labbeana, E. leucarti, E. magna, E. maxima, E. media,
E. meleagridis, E. meleagrimitis, E. mitis, E. necatrix, E
ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E. perforans, E.
phasani, E. piriformis, E. praecox, E. residua, E. scabs, E. spec.,
E. stiedai, E. suis, E. tenella, E. truncata, E. truttae, E.
zuernii, Globidium spec., Isospora belli, L canis, L felis, L
ohioensis, L rivolta, L spec., L suis, Neospora caninum, N. hugesi,
Cystisospora spec., Toxoplasma gondii, Sarcocystis bovicanis, S.
bovihominis, Leucozytozoon simondi, Plasmodium berghei, P.
falciparum, P. malariae, P. ovate, P. vivax, P. spec., Babesia
argentine, B. bovis, B. canis, B. spec., Theileria parva, Theileria
spec., such as Adeleina, for example Hepatozoon canis, H. spec.
[0143] The protozoan genera and species which in pigs lead to
subclinical or clinical infections must be very especially
emphasized, in particular: Eimeria debliecki, E. suis, E. scabs, E.
perminuta, E. spinosa, E. polita, E. porci, E. neodebtiecki,
Isospora suis, Cryptosporidium, Toxoplasma gondii, Sarcocystis
miescheriana, S. suihominis, Babesia trautmanni, B. perroncitoi,
Balantidium coli. Particular examples of economically important
coccidioses are: infections of pigs with coccidia of the genus
Isospora or of cattle with coccidia of the genus Eimeria.
[0144] The compositions according to the invention are effective
against all stages of development of the pathogen.
[0145] A specific object of the invention resides in a use of the
compositions as described above, in treating any disease in a
non-human animal, preferably a microbial disease.
[0146] Another particular object of the invention resides in a use
of the compositions as described above to protect a non-human
animal against coccidiosis, wherein said compositions are
administered orally.
[0147] A particular object of the invention resides in a use of the
compositions as described above to protect a non-human animal
against coccidiosis via parenteral administration, and preferably
by intramuscular or subcutaneous injection.
Storage of the Compositions of the Invention
[0148] The compositions of the invention may be provided in unit
dosage forms (e.g., in single-dose ampoules), in vials containing
several doses or in various containers such as bottles (in which a
suitable preservative may be added). The containers (e.g., bottles)
may be made of glass or of plastic, e.g., polyethylene, and
preferably high density polyethylene (HDPE). Such HDPE bottles may
be, for instance, of nominal capacity of 100 ml, 250 ml, 500 ml,
750 ml or 1000 ml, and closed respectively with polypropylene screw
caps with a tamper-evident seal. Other materials and containers can
also be used for storing compositions of the invention. Such
containers should comply with the strict regulations and
requirements for storing pharmaceutical compositions.
[0149] For example, the compositions of the invention are
preferably stored in multi-layered polymeric stable containers as
described in a patent application no FR2917381. Such containers may
be sterilized by irradiation with or without the composition and
allow a stable conservation of said composition for a long period
of time in sterile conditions. The above containers are in general
formed by the association of several material layers (sheets),
thereby improving the properties of the packagings, which is then
particularly less rigid, less breakable, and more resistant to
heat, to light, to gas and chemical treatments. These multi-layered
containers are made of materials such as polyamides, polyolefin
(PO) (polypropylene (PP), polyethylene (PE)), polyethylene
terephtalate (PET), polyvinyl chloride (PVC), poly(ethylenevinyl
acetate) which are associated with gas barrier layer made of
ethylene vinyl acetate copolymer (copolymer EVOH), ethyl vinyl
acetate (EVA), and polyamides, in order to yield an increased
barrier protection against oxygen and water vapor and limit any
possible alterations of the pharmaceutical composition. In a
specific embodiment, the compositions of the invention are stored
in a multi-layered plastic polymeric container comprising at least
one polyolefin as described in patent application no FR2917381.
[0150] Some compositions, such as injectable compositions, may
require to be sterilized before administration. These compositions
are thus in general manufactured and stored in sterile conditions.
The container may be sterilized either empty or filled with a
composition. Alternatively, the container and the composition may
be sterilized separately, and the container may then be filled in
sterile conditions according to well known methods in the art.
[0151] The container for storing compositions of the invention
preferably maintain properties of resistance after sterilization,
as well as stability, mechanical resistance, transparency, and
impermeability towards environmental factors, chemical products or
various treatments; the reference being the glass material.
[0152] The material for the packaging or container should be
pharmaceutically/veterinary acceptable and should therefore not
alter the quality of the pharmaceutical compositions. Also,
preferably, the compositions should not alter the nature and
composition of the container or packaging in contact therewith.
Such alterations may result in the migration of chemicals from and
to the packaging or container and the composition. Such chemicals
may be impurities, degradation products that appear over time under
the action of oxygen, light and temperature, or due to processing
of the container or packaging, such as sterilization process by
irradiation. These interactions may alter over time the chemical
properties of the composition, such as the stability of the active
ingredient and/or of the container or packaging, transparency
and/or color of the composition or container, thereby reducing the
lifetime of the container or packaging. Furthermore, such
interactions may modify the sterility, safety and efficacy of the
composition.
[0153] The container may contain all of the ingredients of the
compositions in admixture. In particular, the container (e.g.,
flask, bottle, etc.) can comprise, in suspension, the triazine
compound, the further active agent(s) the surfactant(s) and, when
present, the solvent(s) and/or excipient(s).
[0154] Alternatively, the ingredients may be formulated in separate
containers, or in separate compartments of a same container. In
this regard, in a particular embodiment, the invention uses two
containers, a first container comprising the triazine compound, for
instance as a powder, and a second container comprising the other
ingredient(s) in an aqueous suspension with one or more
surfactant(s) having an HLB comprised between 1 and 8. The content
of the two containers are typically mixed prior to
administration.
[0155] In another particular embodiment, the invention uses one
container comprising a first and a second compartments, said
compartments being separated from each other, for instance, by a
membrane or wall, a first compartment comprising the triazine
compound, for instance as a powder, and a second compartment
comprising the other ingredient(s) in an aqueous suspension with
one or more surfactant(s) having an HLB comprised between 1 and 8.
The content of the two compartments are typically mixed prior to
administration, for instance by breaking or removing the separating
membrane or wall.
[0156] Another object of the invention relates to a method for
preparing a composition as defined above, comprising providing a
triazine, a further active ingredient, and a surfactant having an
HLB comprised between 1 and 8, and mixing said ingredients,
generally in an appropriate vehicle or carrier. Typically, the
method comprises (i) providing a triazine compound, preferably in
the form of a powder, (ii) providing the further active ingredient
in an aqueous suspension with one or more surfactant(s) having an
HLB comprised between 1 and 8, and (iii) mixing said ingredients in
an appropriate container. The compositions of the invention may be
prepared in advanced and stored in any appropriate container
(flask, bottle, etc.). Alternatively, the compositions may be
prepared extemporaneously, e.g., by mixing the ingredients shortly
before administration.
[0157] A further object of the invention is a kit comprising one or
several containers as defined above.
Preferred Non-Human Animals Treated by Compositions of the
Invention
[0158] The compositions of the present invention may be used for
the treatment of any non-human animals, including porcine, ovine,
bovine, canine, feline or avian and preferably livestock, breeding
animals, avian animals, companion animals, and laboratory
animals.
[0159] Livestock and breeding animals include non-human mammals
such as, for example, cattle, horses, sheep, pigs, goats, camels,
water buffalos, donkeys, rabbits, fallow deer, reindeer, fur
bearers such as, for example, mink, chinchilla, or raccoon.
[0160] Avian animals include, for example, chickens, hens, ducks,
turkeys, guinea fowl, quail, geese, pigeons or parrots ostriches,
and bird species for keeping in domestic premises and in zoos.
[0161] Companion animals include such as, for example, horses, dogs
and cats.
[0162] Laboratory animals and experimental animals include such as,
for example, mice, rats, guinea pigs, or golden hamsters.
[0163] The compositions of the invention are particularly suited
for treating pigs, ovine, bovine, horses, sheeps, cattle, dogs,
rabbits, or cats.
[0164] The compositions of the invention may be used in adults or
young non-human animals, such as newborn to 10 days old non-human
animals
[0165] Further aspects and advantages of the invention will be
disclosed in the following illustrative experimental section.
Examples
A--Preparation of Compositions
[0166] The following compositions are prepared:
Formula 1
TABLE-US-00001 [0167] Ingredient g/100 mL Toltrazuril 3.5 Iron (as
Gleptoferron) 18.3 Water Qs
Formula 2
TABLE-US-00002 [0168] Ingredient g/100 mL Sorbitan Monooleate 0.3
Toltrazuril 3.5 Iron (as Gleptoferron) 19.4 Water Qs
Formula 3
TABLE-US-00003 [0169] Ingredient g/100 mL Sorbitan Monooleate 0.3
diethylene glycol monoethyl ether 10 Toltrazuril 3.5 Iron (as
Gleptoferron) 17.8 Water Qs
Formula 4
TABLE-US-00004 [0170] Ingredient g/100 mL Sorbitan Monooleate 0.3
diethylene glycol monoethyl ether 10 Copolymer Polyoxyl 35 -
hydrogenated castor oil 0.1 Toltrazuril 3.5 Iron (as Gleptoferron)
17.8 Water Qs
Formula 5
TABLE-US-00005 [0171] Ingredient g/100 mL Sorbitan Monooleate 0.3
Copolymer Polyoxyl 35 - hydrogenated castor oil 0.1 Toltrazuril 3.5
Iron (as Gleptoferron) 19.4 Water Qs
Formula 6:
TABLE-US-00006 [0172] Ingredient g/100 mL Sorbitan Monooleate 0.1
Sodium chloride 1.0 Diethylene glycol monoethyl ether 10
Toltrazuril 3.5 Iron (as Gleptoferron) 17.8 Water Qs
Formula 7:
TABLE-US-00007 [0173] Ingredient g/100 mL Propylene glycol
monolaurate 0.3 Sodium chloride 1.0 Copolymer Polyoxyl 35 -
hydrogenated castor oil 0.1 Toltrazuril 3.5 Iron (as Gleptoferron)
19.3 Water Qs
Formula 8:
TABLE-US-00008 [0174] Ingredient g/100 mL Sorbitan Monooleate 0.3
Copolymer Polyoxyl 35 - hydrogenated castor oil 0.1 Toltrazuril 3.5
Iron (as dextran) 19.4 Water Qs
Formula 9:
TABLE-US-00009 [0175] Ingredient g/100 mL Sodium docusate 0.1
Silicone emulsion 0.1 Sodium chloride 1.5 Iron (as gleptoferron)
13.5 Toltrazuril 4.2 Water qs
Formula 10:
TABLE-US-00010 [0176] Ingredient g/100 mL Sodium docusate 0.1
Silicone emulsion 0.1 Sodium chloride 1.0 Diethylene glycol
monethyl ether 5.0 Iron (as gleptoferron) 13.5 Toltrazuril 4.2
water qs
Formula 11:
TABLE-US-00011 [0177] Ingredient g/100 mL Sodium docusate 0.2
Simethicone emulsion 0.1 Sodium chloride 0.5 Povidone 1.0 Colloidal
silicon dioxide 0.5 Phenol 0.6 Iron (as gleptoferron) 13.5
Toltrazuril 4.2 Water QS
Formula 12:
TABLE-US-00012 [0178] Ingredient g/100 mL Sodium docusate 0.2
Simethicone emulsion 0.1 Sodium chloride 1.0 Povidone 1.0 Colloidal
silicon dioxide 0.5 Phenol 0.6 Iron (as gleptoferron) 13.5
Toltrazuril 4.2 Water QS
Formula 13:
TABLE-US-00013 [0179] Ingredient g/100 mL Sodium docusate 0.1
Simethicone emulsion 0.1 Sodium chloride 1.0 Povidone 1.0 Colloidal
silicon dioxide 0.5 Phenol 0.6 Iron (as gleptoferron) 13.5
Toltrazuril 4.2 Water QS
Formula 14:
TABLE-US-00014 [0180] Ingredient g/100 mL Sodium docusate 0.1
Simethicone emulsion 0.1 Sodium chloride 1.0 Povidone 1.0 Colloidal
silicon dioxide 0.5 Phenol 0.6 Iron (as gleptoferron) 18.8
Toltrazuril 2.9 Water QS
B-- Evaluation of the Foaming Properties of the Compositions
[0181] The foaming aspect of the formulations is estimated
according to the following procedure: [0182] Filling of graduated
test-tube with 7 g of product. [0183] Vigorous agitation of the
test-tube during 45 seconds. [0184] Measuring of the foam formed at
the following time intervals: [0185] right after agitation, [0186]
1 minute after agitation, [0187] 3 minutes after agitation, [0188]
5 minutes after agitation, [0189] 10 minutes after agitation
[0190] The results are presented in the following Table.
TABLE-US-00015 Formula 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time Foam
height (mm) 0 min 32 3 2.5 2 3 2 4 3 15 15 20 19 20 6 1 min 34 3 2
2 2 2 1 2 1 0 17 17 9 4 3 min 34 3 1.5 1.5 2 2 1 2 0 0 15 2 3 2 5
min 33 3 1 1 1.5 2 1 2 0 0 5 1 2 2 10 min 33 2.5 0.5 0.5 1 1 0 2 0
0 1 0 0 0
[0191] Formula 1, which does not contain a low HLB surfactant
according to the invention, exhibits high foaming 10 minutes after
agitation. In contrast, Formula 2 to 8 have a foam height below 3
mm after 10 minutes, and have therefore remarkable antifoaming
properties.
[0192] Formula 3, 4, 7 and 11 to 14 are remarkable since they are
characterized by a rapid decrease of the foam thickness, which
almost disappeared 10 minutes post agitation.
[0193] Formula 9 and 10 are particularly remarkable since they are
characterized by a very fast decrease of the foam thickness, which
almost disappeared 1 to 3 minutes post agitation
[0194] The formation of foams when reconstituting liquid dosage
formulations is undesirable and disruptive. The remarkable capacity
with the formulations of the invention to avoid and/or quickly stop
formation of foam in an aqueous suspension after reconstitution is
therefore particularly advantageous since it allows the user to
quickly syringe the suspension in optimal condition, to secure the
toltrazuril and iron dose taken, and to minimize the phenomenon of
re-suspension observed after the agitation.
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